Synthesis and reactivity of 4-amino-substituted furfurals

Article abstract of DOI:10.1021/jo4026308

γ-Hydroxy α,β-unsaturated acetylenic ketones have been converted to 4-amino-substituted furfurals by reaction with secondary amines followed by treatment with acid in a mixture of THF and water. The stability of the furfurals depends to some extent on the nature of the amino group, whereas the reactivity has been shown to be reagent-dependent. When treated with phosphorus ylids, the expected alkenes are formed with E configuration in high yields, but when exposed to nitroalkanes under basic conditions (the Henry reaction) abnormal transformations appear to occur, and 2-acylated furans are obtained, albeit in low yield, instead of nitroalkanols.

Full text of DOI:10.1021/jo4026308

Article
pubs.acs.org/joc
Synthesis and Reactivity of 4‑Amino-Substituted Furfurals
Uranbaatar Erdenebileg, Inger Høstmark, Karina Polden, and Leiv K. Sydnes*
́
Department of Chemistry, University of Bergen, Allegaten 41, NO-5007 Bergen, Norway
S
* Supporting Information
ABSTRACT: γ-Hydroxy α,β-unsaturated acetylenic ketones have been converted to
4-amino-substituted furfurals by reaction with secondary amines followed by
treatment with acid in a mixture of THF and water. The stability of the furfurals
depends to some extent on the nature of the amino group, whereas the reactivity has
been shown to be reagent-dependent. When treated with phosphorus ylids, the
expected alkenes are formed with E configuration in high yields, but when exposed to nitroalkanes under basic conditions (the
Henry reaction) abnormal transformations appear to occur, and 2-acylated furans are obtained, albeit in low yield, instead of
nitroalkanols.
1-hydroxyalkyl group. Hydroxyketones 2, if formed, are
expected to be labile and undergo cyclization and hemiketal
formation and finally form furans (3) rather easily under the
right conditions (Scheme 1). What will happen if 1 is treated
with a primary amine, however, is less clear because in such a
case the resulting secondary amino moiety and the hydroxyl
group can become involved in intramolecular hydrogen
bonding with the carbonyl group and end up cis to the
carbonyl moiety.
INTRODUCTION
■
Unsaturated, conjugated motifs constitute an important group
of reactive substructures in organic synthesis. One such
structure that has been relatively little utilized but now is
gaining more attention is the α,β-unsaturated acetylenic
ketones.1−3 After having worked out several high-yield
syntheses of a variety of such compounds, employing 3,3,4,4-
tetraethoxybut-1-yne as starting material,2 the study of synthetic
transformations of such ketones has been a priority in our
group.3 This has led to a growing body of interesting results
including several furan syntheses,4,5 and here we report a new
regiospecific synthesis of 4,5-disubstituted furfurals.
The basis for the synthesis was the discovery that when 1,1-
diethoxybut-3-yn-2-one was reacted with primary and secon-
dary amines, even in significant excess, only monoaddition
occurred and gave the corresponding 4-amino-substituted 1,1-
diethoxybut-3-en-2-ones.5 Not only was the yield high, but also
the reaction was stereospecific in the sense that ammonia and
all the primary amines investigated afforded only the
corresponding Z alkene, whereas the secondary amines
furnished the E isomer (Scheme 1).
RESULTS AND DISCUSSION
■
In order to test these predictions, exploratory experiments were
performed by treating 1,1-diethoxy-5-hydroxyhex-3-yn-2-one
(Scheme 1, R1 = Me; 1b) with methylamine and diethyl-amine
under various conditions. Both amines reacted fairly quickly,
but the outcome was quite different; whereas the latter gave
one product only, viz. 2-diethoxymethyl-4-(diethyl-amino)furan
(3b), methylamine afforded a 5:3 mixture of compounds, the
structures of which were elucidated to be the E and Z isomers
of a hydroxyketone, 1,1-diethoxy-5-hydroxy-4-(methylamino)-
1
hex-3-en-2-one, on the basis of H spectra of crude product
mixtures from several reactions. Isolation of 3b was
straightforward by flash chromatography, but attempts to
isolate the isomers of the hydroxyketone were totally
unsuccessful; instead a single isomer of 1,1-diethoxy-4-
(methylamino)hex-3-ene-2,5-dione, conceivably the Z isomer
due to the chemical shift of the olefinic proton,6 was obtained.
On the basis of these observations, we decided to investigate
reactions with secondary amines first, and the results from these
studies are reported here.
A reasonable consequence of this specificity should be that if
secondary amines react with 1,1-diethoxy-5-hydroxyalk-3-yn-2-
ones (1), the primary products should be the corresponding
(3E)-1,1-diethoxy-4-dialkylamino-5-hydroxyalk-3-en-2-ones (2)
because the carbonyl moiety is sterically repelled from the
dialkylamino group but attracted by hydrogen bonding to the
Scheme 1. Michael Addition of Amines to α,β-Unsaturated
Acetylenic Ketones
Four other 5-substituted derivatives of 1a were then reacted
with diethylamine under conditions identical to those applied
when 1b was reacted, and without exception the substrates
reacted quickly and furnished a single product, viz. the
corresponding 5-R-substituted furan 3, in quite good yields
(Table 1). There were no traces of the anticipated intermediate
Received: November 28, 2013
© XXXX American Chemical Society
A
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Table 1. Synthesis of 4-Diethylaminofurfural Diethyl Acetals
(3) from 1,1-Diethoxy-5-hydroxyalk-3-yn-2-ones (1)
Scheme 2
Furfurals are useful compounds in synthesis,7 and the
formation of 4 when 3 is stored under moist conditions
encouraged us to prepare the furfurals from 3. A number of
methods are available for this transformation,8 and after some
exploratory experiments with 3b we settled for treating 3 with
p-TsOH in a mixture of THF and water at 40 °C, which
appeared to give 4b in good yield (77%). All the other
aminofuran acetals were then reacted under these conditions,
and with two exceptions the corresponding furfural was
obtained in 76−80% isolated yield (Table 3). One of the
R
1,3
reaction time (h)
isolated yield (%)
H
a
b
c
1.0
0.5
1.0
1.0
1.0
70
81
78
77
75
Me
i-Pr
n-C6H13
Ph
d
e
products, the corresponding isomeric Michael adducts, in any
of the reactions, and this indicates that the carbonyl group is
activated toward nucleophilic attack by the diethoxymethyl
group attached to it.
Table 3. Preparation of 4-Amino-Substituted Furfurals (4)
from 4-Amino-Substituted Furfural Diethyl Acetals (3)
The scope of the transformation was further investigated by
reacting 1b with a few additional secondary amines. It appeared
that piperidine, morpholine, and pyrrolidine were almost as
efficient as diethylamine and furnished the expected 4-
aminosubstituted furfural diethyl acetals, 3f, 3g, and 3h,
respectively, in fairly good yields (Table 2, entries 1−3).
However, when less nucleophilic secondary amines were
employed, e.g., diphenylamine, no reaction occurred at all
(Table 2, entry 4).
reaction time
(h)
isolated yield
(%)
R
3
R1,R2
4
H
a
b
c
d
e
f
Et,Et
Et,Et
Et,Et
Et,Et
Et,Et
1.0
1.0
1.0
1.5
1.0
1.0
1.0
1.0
a
b
c
d
e
f
0
Me
77
89
80
78
76
76
55
i-Pr
Table 2. Preparation of 4-Amino-Substituted 5-
Methylfurfural Diethyl Acetals (3; R = Me) from 1,1-
Diethoxy-5-hydroxyhex-3-yn-2-one (1a)
n-C6H13
Ph
Me
(CH2)5
Me
g
h
(CH2)2O(CH2)2
(CH2)4
g
h
Me
exceptions was again pyrrolidinyl acetal (3f), which suffered
partial decomposition and furnished the corresponding furfural
4f in 55% yield only. The other exception was 2-
diethoxymethyl-4-diethylaminofuran (3a), which underwent
complete destruction under acidic conditions and gave an
intractable product mixture, from which not even a small
amount of furfural 4a could be isolated (Table 3). Not
surprisingly, the yield of the furfurals could be improved by
performing the two-step preparation in a one-pot synthesis
from 1. For instance, when 4b was prepared in this way from
1b, the overall yield increased from 62 to 73%.
A likely consequence of the mechanistic sketch in Scheme 1
is that if the propargylic alcohol is tertiary, no furan formation
will take place because dehydration becomes unlikely. And
indeed, when 1,1-diethoxy-5-hydroxy-5-methylhex-3-yn-2-one
(1f) was treated with diethylamine, only cyclization and no
aromatization occurred, and 4-ethoxy-2-diethoxymethyl-4-
diethylamino-4,5-dihydro-5,5-dimethylfuran (6) was obtained
in 86% yield. This compound appeared not to be stable unless
it was dried thoroughly, so if exposed to air under ambient
conditions 6 was gradually converted to the corresponding
ketone, 5-(diethoxymethyl)-2,2-dimethylfuran-3(2H)-one (7).
A conceivable reaction pathway for the formation of 7 is
outlined in Scheme 3.
entry
NR2
3
reaction time (h)
isolated yield (%)
1
2
3
4
piperidin-1-yl
morpholin-4-yl
pyrrolidin-1-yl
diphenylamino
f
1.0
1.0
1.0
3.0
69
66
60
0
g
h
The stability of acetals 3 appeared to be amine-dependent in
the sense that all the furans except pyrrolidine derivative 3h
were stable when kept dry in closed vials at and below room
temperature. Why 3h is so special is still not clear, but a key
point is probably that the interaction between the nitrogen
electron pair and the π system in the furan ring is different for
this compound because of conformational constraints imposed
by the butylene chain in the pyrrolidine ring. However, several
other 4-aminofurfural diethyl acetals stored at room temper-
ature with access to air and moisture turned out to be unstable
and appeared to be gradually converted to at least two
products, the corresponding furfural 4 and a diketone. For
instance, the two compounds formed in the case of 5-
diethoxymethyl-3-diethylamino-2-methylfuran (3b) were 4-
diethylamino-5-methylfuran-2-carbaldehyde (4b) and a com-
pound believed to be 1,1-diethoxy-4-diethylaminohex-3-ene-
2,5-dione (5) (Scheme 2). Both compounds can be envisaged
to have been formed by transformations with significant
literature precedence, deacetalization of the acetal moiety, and
oxidative ring cleavage of the furan ring, respectively.
Structurally aminofurfurals 4 are interesting compounds
because there are both electron-withdrawing and electron-
donating substituents attached to the aromatic ring. Overall this
will give a push−pull system, which conceivably could lead to
B
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Scheme 3
chemical properties different from those exhibited by furfural
itself. In order to explore if this is the case, selected 4-
aminofurfurals are being used as substrates in various reactions
with carbanions. So far the Wittig and Henry reactions, known
to furnish the corresponding 2-(1-alkenyl)furans and 1-furfuryl-
2-nitroalkan-1-ols, respectively, when furfural itself is re-
acted,9,10 have been most extensively investigated.
The Wittig-type reactions were performed by treating
selected 4-aminofurfurals with benzylidenetriphenylphosphor-
ane and the phosphonate carbanion from triethyl phosphono-
acetate under standard conditions. In all cases the reactions
proceeded smoothly and gave the expected alkenyl-substituted
furans 8 in good to excellent yield (Table 4). It is noteworthy
the coupling constant for the vicinal H−H coupling across the
C−C double bond, which was 16.2 or 16.3 Hz for the styrenyl-
substituted furans (8a−8d) and 15.6 or 15.7 Hz for the acrylate
derivatives (8e−8h).12
Two of the 4-aminofurfurals, 4b and 4e, were then reacted
with some nitroalkanes under basic conditions (the Henry
reaction), and on the basis of literature precedence,10 formation
of the corresponding 2-nitroalkan-1-ols and/or 2-nitroalk-1-
enes was the anticipated outcome (Scheme 4, path A).
However, to our surprise such products were not obtained;
in every case except one a complex reaction mixture was
obtained, and only one product, an alkyl furan-2-yl ketone (9),
could be structure elucidated and isolated in moderate yield
(Table 5). The only exception to this rule was 4b, which when
reacted with nitromethane under basic conditions gave one
product in addition to the alkyl furan-2-yl ketone, viz. 3-
diethylamino-5-hydroxy-iminoacetyl-2-methylfuran (10)
(Scheme 4, path B).
Table 4. Preparation of 2-Ethenylfuran Derivatives 8 by
Treating 4-Amino-Substituted Furfurals 4 with Phosphorous
a
Reagents
Formation of 9 has little literature precedence, but a similar
transformation was reported by Nomland and Hills, who
obtained 2-acylquinoline instead of the Henry product when
quinoline-2-carbaldehyde was treated with nitroalkanes under
basic conditions.13 The total oxidation state of the carbon
atoms in the acyl groups is identical to that of the carbon atoms
in their precursors, the nitroalkanol moieties, and this indicates
that the acyl groups is formed from the Henry products by
HNO2 elimination. When this rationale is applied to explain the
formation of 9, transition state 11 and enol 12 are invoked as
intermediates when 4b is used as an example (Scheme 5). The
much lower yields obtained when nitroethane and 1-nitro-
butane are applied is probably due to conformational effects
caused by steric interactions between neighboring groups; these
effects will make it more difficult to achieve the gauche-like
relationship required between the hydrogen atom and the nitro
group, and this slows down the nitrous-acid elimination.
Oxime 10, however, results from a much more deep-seated
transformation since both carbon atoms in the likely 2-
nitroethanol intermediate 11 are oxidized, whereas the nitrogen
atom is reduced. The ability of the nitro group to function as an
oxidizing agent is well established.14 A conceivable reaction
mechanism for formation of 10 is depicted in Scheme 6.
isolated yield
4
R
R1,R2
reagent
R3
Ph
8
(%)
b
f
Me
Me
Me
Ph
Et,Et
BTP
BTP
BTP
BTP
TPA
TPA
TPA
TPA
a
b
c
d
e
f
89
60
90
50
60
84
85
84
(CH2)5
Ph
g
e
b
f
(CH2)2O(CH2)2
Et,Et
Ph
Ph
Me
Me
Me
Ph
Et,Et
CO2Et
CO2Et
CO2Et
CO2Et
(CH2)5
g
e
(CH2)2O(CH2)2
Et,Et
g
h
a
Reactions were performed with benzylidenetriphenylphosphorane
(BTP) and the phosphonate carbanion from triethyl phosphonoace-
tate (TPA).
that the best yield with both reagents was obtained when 4g
was reacted. This furfural contains a morpholine moiety that is
much less basic than both piperidine and diethylamine, the
other bases attached to the furan ring in 4 (pKb is 5.70 for
morpholine compared to 3.02 for piperidine and 2.71 for
diethylamine).11 On the basis of these pKb values, it is
conceivable that the electron density of the formyl group
increases less in 4g than in the other furfurals, rendering its
carbonyl group more electrophilic and more reactive in Wittig
reactions. It is also interesting to note that all reactions were
stereospecific and furnished the expected alkenes with E
configuration; the stereochemistry was borne out by the size of
EXPERIMENTAL SECTION
■
Unless otherwise noted all reagents were commercially available and
used as received. THF was dried and distilled from Na/benzophenone
under nitrogen. TLC analyses were performed with silica gel (60 F254
)
on aluminum sheets, and an ethanol solution of phosphor
C
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Article
Scheme 4
washed with a saturated aqueous solution of NaHCO3 (80 mL), dried
over MgSO4, filtered and evaporated under reduced pressure, affording
a crude product, which was essentially pure 1. Following this
procedure 1a−e were prepared.
Table 5. Preparation of Alkyl Furan-2-yl Ketones by
Treating 4-Amino-Substituted Furfurals 4 with Nitroalkanes
under Basic Conditions
1,1-Diethoxy-5-hydroxypent-3-yn-2-one (1a). 4,4,5,5-Tetraethox-
ypent-2-yn-1-ol (2.0 g, 7.7 mmol) was refluxed for 3.0 h and gave
essentially pure 1a (1.33 g, 93%) as a yellowish liquid without
purification: IR (film) 3449 (s), 2211 (s), 1693 (s), 1480 (w), 1444
(m), 1394 (m), 1373 (m), 1321 (m), 1250 (s), 1167 (s), 1112 (s),
1058 (s), 961 (w), 906 (w) cm−1; 1H NMR (400 MHz, CDCl3) δ 4.72
(s, 1H), 4.48 (s, 2H), 3.78−3.60 (m, 4H), 2.00 (bs, 1H), 1.28 (t, J =
7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 182.6, 101.8, 94.2, 82.8,
4
R
R2
reaction time (h)
9
isolated yield (%)
a
b
b
e
Me
Me
Ph
Me
Et
6
a
b
c
66
12
24
24
38
37
18
+
63.6, 51.0, 15.2; HRMS Calcd for C9H14O4 [M + H]+ 187.09703,
Et
found 187.09852.
b
Me
Bu
d
1,1-Diethoxy-5-hydroxyhex-3-yn-2-one (1b). 5,5,6,6-Tetraethoxy-
hex-3-yn-2-ol (2.0 g, 7.3 mmol) was refluxed for 3.0 h and gave
esentially pure 1b (1.31 g, 90%) as a yellowish liquid without
purification: IR (film) 3443 (s), 2216 (s), 1689 (s), 1480 (w), 1446
(m), 1394 (m), 1372 (m), 1325 (m), 1247 (m), 1167 (s), 1122 (s),
a
In addition 3-diethylamino-5-(N-hydroxyiminoacetyl)-2-methylfuran
(10) was isolated in 18% yield.
polymolybdic acid was used as visualizing agent. Flash chromatography
(FC) was carried out with silica gel (230−400 mesh) as the stationary
phase and mixtures of either hexanes and ethyl acetate or
dichloromethane and methanol as the mobile phase. The eluent
composition is given in each case. IR absorptions are given in wave
numbers (cm−1), and intensities are characterized as (s) for strong,
1
1102 (s), 1068 (s), 952 (w), 913 (w) cm−1; H NMR (400 MHz,
CDCl3) δ 4.74 (s, 1H), 4.71 (q, J = 6.7 Hz, 1H), 3.77−3.60 (m, 4H),
2.09 (bs, 1H), 1.53 (d, J = 6.7 Hz, 3H), 1.28 (t, J = 7.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 182.8, 101.8, 97.2, 81.2, 63.5, 58.3, 23.4,
+
15.3; HRMS Calcd for C10H17O4 [M + H]+ 201.11268, found
1
201.11204.
(m) for medium, (w) for weak. H NMR spectra were recorded at
1,1-Diethoxy-5-hydroxy-6-methylhept-3-yn-2-one (1c). 6,6,7,7-
Tetraethoxy-2-methyl-hept-4-yn-3-ol4 (2.0 g, 6.6 mmol) was refluxed
for 3.0 h and gave essentially pure 1c (1.37 g, 91%) as a yellowish
liquid without purification: IR (film) 3437 (s), 2210 (s), 1693 (s),
1469 (m), 1446 (m), 1387 (m), 1371 (m), 1347 (m), 1320 (m), 1245
(m), 1164 (s), 1108 (s), 1067 (s), 960 (w), 926 (w), 900 (w) cm−1;
1H NMR (400 MHz, CDCl3) δ 4.74 (s, 1H), 4.36 (t, J = 5.8 Hz, 1H),
3.76−3.60 (m, 4H), 2.04−1.94 (m, 2H) 1.27 (t, J = 7.0 Hz, 6H), 1.06
(d, J = 6.6 Hz, 3H), 1.04 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 182.9, 101.7, 95.9, 82.9, 67.9, 63.3, 34.5, 18.2, 17.7, 15.3;
ambient temperature at 400 MHz with TMS as the internal reference
(δH = 0.00 ppm). Chemical shifts are reported downfield from TMS,
and coupling constants are given in Hz. Multiplicity is given as (s) for
singlet, (d) for doublet, (t) for triplet, (q) for quartet, (dd) for doublet
of doublets, and (m) for multiplet. 13C NMR spectra were recorded at
ambient temperature at 100 MHz with the central peak of CDCl3
triplet (δC = 77.23 ppm) as the internal reference. Mass spectra were
obtained on a TOF MS high-resolution mass spectrometer operated in
the DART/ESI+ mode with ionization potential 70 eV.
Synthesis of Hydroxyketones 1 from the Corresponding
4,4,5,5-Tetraethoxyalk-3-yn-1-ols; General Procedure. The
4,4,5,5-tetraethoxyalk-3-yn-1-ol derivative (2.0 g) was dissolved in a
7:3 mixture of THF and water (100 mL). p-Toluenesulfonic acid
monohydrate (0.2 equiv) was added, and the mixture was refluxed
until all the starting material had been consumed (followed by TLC).
Most of the THF was then evaporated under reduced pressure on a
rotary evaporator. To the residue was added brine (30 mL) and DCM
(30 mL). The phases were separated, and the aqueous phase was
extracted with DCM (3 × 20 mL). The combined extracts were
+
HRMS Calcd for C12H20O4 [M + H]+ 229.14398, found 229.14386.
1,1-Diethoxy-5-hydroxyundec-3-yn-2-one (1d). 1,1,2,2-Tetrae-
thoxyundec-3-yn-5-ol (2.0 g, 5.8 mmol) was refluxed for 3 h and
gave 1d (1.49 g, 95%) as a reddish liquid without any purification: IR
(film) 3436 (s), 2211 (s), 1760 (w), 1690 (s), 1479 (w), 1467 (m),
1457 (m), 1445 (m), 1393 (m), 1374 (m), 1319 (m), 1245 (m), 1162
(s), 1110 (s), 1066 (s), 907 (w) cm−1; 1H NMR (400 MHz, CDCl3) δ
4.73 (s, 1H), 4.55 (q, J = 6.7 Hz, 1H), 3.76−3.60 (m, 4H), 1.98 (bs,
1H), 1.82−1.26 (m, 16H), 0.89 (t, J = 6.7 Hz, 3H); 13C NMR (100
Scheme 5
D
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The Journal of Organic Chemistry
Article
Scheme 6
MHz, CDCl3) δ 182.9, 101.8, 96.6, 82.2, 63.4, 62.6, 37.1, 31.8, 29.0,
(0,073 g, 1.0 mmol). Isolation by FC (hexanes/ethyl acetate 90:10)
provided the title compound (0.207 g, 81%) as a yellow liquid: IR
(film) 1709 (w), 1639 (m), 1633 (m), 1579 (m), 1526 (m), 1477 (m),
1445 (s), 1404 (m), 1372 (s), 1338 (s), 1294 (m), 1277 (m), 1238
(s), 1228 (s), 1184 (m), 1174 (m), 1161 (m), 1121 (s), 1091 (s),
1055 (s), 1007 (s), 988 (m), 954 (m), 904 (m) cm−1; 1H NMR (400
MHz, CDCl3) δ 6.31 (s, 1H), 5.43 (s, 1H), 3.67−3.54 (m, 4H), 2.79
(q, J = 7.1 Hz, 4H), 2.21 (s, 3H), 1.24 (t, J = 7.1 Hz, 6H), 0.93 (t, J =
7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 148.6, 146.4, 131.1,
+
25.1, 22.7, 15.3, 14.2; HRMS Calcd for C15H26O4 [M + H]+
271.19093, found 271.19193.
1,1-Diethoxy-5-hydroxy-5-phenylpent-3-yn-2-one (1e). 4,4,5,5-
Tetraethoxy-1-phenyl-pent-2-yn-1-ol (2.0 g, 5.9 mmol) was refluxed
for 5.0 h and afforded 1e (1.51 g, 95%) as a yellow liquid: IR (film)
3429 (s), 3088 (w), 3064 (m), 3032 (m), 2978 (s), 2931 (s), 2896 (s),
2210 (s), 1694 (s), 1601 (w), 1494 (s), 1480 (m), 1453 (s), 1393 (m),
1373 (m), 1321 (m), 1293 (m), 1244 (m), 1160 (s), 1109 (s), 1065
(s), 919 (m), 837 (m), 818 (m) 763 (m), 700 (s), 655 (m), 600 (m)
+
105.2, 96.8, 61.4, 50.3, 15.4, 13.4, 11.5; HRMS Calcd for C14H26NO3
[M + H+] 256.19127, found 256.18940.
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.57- 7.35 (m, 5H), 5.65 (s,
5-Diethoxymethyl-3-diethylamino-2-isopropylfuran (3c). Com-
pound 1c (0.227 g, 1.00 mmol) was reacted with diethylamine
(0,073 g, 1.0 mmol). Isolation by FC (hexanes/ethyl acetate 90:10)
provided the title compound (0.220 g, 78%) as a yellow liquid: IR
(film) 1628 (w), 1576 (w), 1476 (m), 1446 (m), 1404 (m), 1371 (s),
1339 (s), 1240 (s), 1160 (m), 1122 (s), 1091 (s), 1054 (s), 1025 (m),
1H), 4.76 (s, 1H), 3.77−3.60 (m, 4H), 2.47 (bs, 1H), 1.27 (t, J = 7.0
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 182.8, 138.8, 129.1, 127.7,
127.1, 101.8, 94.6, 83.4, 64.7, 63.4, 15.3, 15.1; HRMS Calcd for
+
C13H13O3 [M − OEt]+ 217.08647, found 217.08856.
Reaction of 1,1-Diethoxy-5-hydroxyhex-3-yn-2-one (1b)
with Methylamine. Hydroxy-ketone 1b (0.200 g, 1.0 mmol) was
dissolved in ethanol (5 mL), and a 40% (w/w) aqueous solution of
methylamine (0.080 g, 1.0 mmol) was added under stirring at rt in the
presence of air. The mixture was then stirred at rt until all the starting
material had been consumed as judged from TLC (15 min). After
drying (MgSO4) and filtration the solvent was evaporated on a rotary
1
1006 (m), 979 (m), 906 (m), 873 (w) cm−1; H NMR (400 MHz,
CDCl3) δ 6.31 (s, 1H), 5.46 (s, 1H), 3.64−3.52 (m, 4H), 3.12 (septet,
J = 7.0 Hz, 1H), 2.75 (q, J = 7.1 Hz, 4H), 1.23−1.18 (m, 12H) 0.92 (t,
J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 155.5, 148.7, 128.8,
104.8, 96.8, 61.1, 50.9, 25.3, 21.5, 15.4, 13.6; HRMS Calcd for
1
+
C16H30NO3 [M + H+] 284.22257, found 284.22481.
evaporator, and a H NMR spectrum of the residue was recorded
1
before isomer separation by FC was attempted: H NMR (400 MHz,
5-Diethoxymethyl-3-diethylamino-2-hexylfuran (3d). Compound
1d (0.270 g, 1.00 mmol) was reacted with diethylamine (0,073 g, 1.0
mmol). Isolation by FC (hexanes/ethyl acetate 95:5) provided the title
compound (0.250 g, 77%) as a yellow liquid: IR (film) 1637 (m), 1576
(m), 1455 (m), 1445 (m), 1403 (m), 1372 (m), 1358 (m), 1338 (m),
1239 (m), 1225 (m), 1172 (m), 1123 (s), 1092 (s), 1055 (s), 1010
(s), 977 (m), 913 (m), 889 (w) cm−1; 1H NMR (400 MHz, CDCl3) δ
6.32 (s, 1H), 5.45 (s, 1H), 3.66−3.53 (m, 4H), 2.78 (q, J = 7.1 Hz,
4H), 2.57 (t, J = 7.6 Hz, 2H), 1.61−1.57 (m, 2H), 1.35−1.25 (m, 6H),
1.22 (t, J = 7.1 Hz, 6H), 0.93 (t, J = 7.1 Hz, 6H), 0.89−0.85 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 151.0, 148.7, 130.7, 105.0, 96.8, 61.2,
50.6, 31.9, 29.3, 28.5, 25.7, 22.8, 15.4, 14.3, 13.5; HRMS Calcd for
CDCl3) δ 10.90 and 6.00 (2 bs in a 5:3 ratio, 1H, NH), 5.67 and 5.35
(2 bs in a 5:3 ratio, 1H), 5.20 and 4.63 (2 m in a 5:3 ratio, 1H), 3.8−
3.5 (m, 4H), 3.01 (d, J = 5.6 Hz, 3H), 2.43 (s, 3H), 1.3−1.2 (m, 6H).
Separation by FC (hexanes/ethyl acetate 80:20) gave only one
product, 1,1-diethoxy-4-(methylamino)hex-3-ene-2,5-dione, (0.121 g,
53%), as an orange liquid: IR (film) 3273 (s), 3082 (m), 1712 (s),
1616 (s), 1573 (s), 1535 (s), 1429 (s), 1358 (s), 1317 (s), 1164 (s),
1
1102 (s), 1063 (s), 969 (m), 901 (m) cm−1; H NMR (400 MHz,
CDCl3) δ 10.25 (bs, 1H), 5.68 (s, 1H), 4.67 (s, 1H), 3.74−3.56 (m,
4H), 3.01 (d, J = 5.6 Hz, 3H), 2.43 (s, 3H), 1.25 (t, J = 7.0 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 198.3, 194.6, 160.5, 102.3, 89.8, 62.8,
+
C19H36NO3 [M + H+] 326.26952, found 326.27266.
+
31.7, 29.1, 15.4; HRMS Calcd for C11H20NO4 [M + H+] 230.13923,
5-Diethoxymethyl-3-diethylamino-2-phenylfuran (3e). Com-
pound 1e (0.262 g, 1.00 mmol) was reacted with diethylamine
(0,073 g, 1.0 mmol). Isolation by FC (hexanes/ethyl acetate 95:5)
provided the title compound (0.237 g, 75%) as a yellow liquid: IR
(film) 3057 (w), 3026 (w) 1614 (m), 1492 (m), 1474 (m), 1402 (m),
1372 (s), 1357 (s), 1337 (s), 1175 (m), 1158 (m), 1132 (s), 1117 (s),
1093 (s), 1056 (s), 1034 (s), 1005 (m), 992 (m), 985 (m), 907 (m),
found 230.14050.
Synthesis of Furfural Diethyl Acetals (3) from 1; General
Procedure. γ-Hydroxy-α,β-unsaturated acetylenic ketone (1) (1−2
mmol) was dissolved in ethanol (5 mL), and amine (1.0 mol equiv)
was added under stirring at rt in the presence of air. The reaction
mixture was subsequently stirred at rt until all the starting material had
been consumed as judged from TLC (0.5−1.0 h, see Table 1). The
solvent was then evaporated, and from the residue the product was
isolated by FC.
1
881 (w) cm−1; H NMR (400 MHz, CDCl3) δ 8.08−8.06 (m, 2H),
7.37−7.33 (m, 2H), 7.20−7.16 (m, 1H), 6.52 (s, 1H), 5.54 (s, 1H),
3.72−3.58 (m, 4H), 2.92 (q, J = 7.1 Hz, 4H), 1.25 (t, J = 7.0 Hz, 6H),
1.01 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 149.8, 144.9,
134.6, 131.7, 128.3, 126.5, 124.6, 106.9, 96.8, 61.5, 49.1, 15.4, 13.0;
HRMS Calcd for C19H28NO3+ [M + H+] 318.20692, found 318.20960.
1-(5-Diethoxymethyl-2-methylfuran-3-yl)piperidine (3f). Com-
pound 1b (0.201 g, 1.00 mmol) was reacted with piperidine (0,085
g, 1.0 mmol). Isolation by FC (hexanes/ethyl acetate 95:5) provided
the title compound (0.185 g, 69%) as a yellow liquid: IR (film) 2792
(s), 2744 (m), 1634 (m), 1572 (m), 1452 (m), 1442 (s), 1403 (m),
1381 (s), 1372 (s), 1342 (m), 1294 (m), 1271 (m), 1261 (m), 1225
(s), 1163 (m), 1154 (m), 1114 (s), 1098 (s), 1056 (s), 1008 (m), 988
(m), 955 (m), 905 (m), 866 (w) cm−1; 1H NMR (400 MHz, CDCl3)
δ 6.31 (s, 1H), 5.40 (s, 1H), 3.67−3.53 (m, 4H), 2.79−2.76 (m, 4H),
2.25 (s, 3H), 1.68−1.62 (m, 4H), 1.51−1.46 (m, 2H), 1.23 (t, J = 7.0
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 148.0, 141.0, 135.7, 104.3,
2-Diethoxymethyl-4-(diethylamino)furan (3a). Compound 1a
(0.373 g, 2.00 mmol) was reacted with diethylamine (0,146 g, 2.00
mmol) for 1 h. Isolation by FC (hexanes/ethyl acetate 90:10)
provided the title compound (0.337 g, 70%) as an orange liquid. The
spectroscopic data are in accordance with those reported in the
literature: IR (film) 3100 (w), 1763 (s), 1620 (s), 1545 (s), 1447 (s),
1374 (s), 1342 (s), 1277 (s), 1226 (m), 1176 (s), 1139 (s), 1107 (s),
1058 (s), 1030 (s), 980 (m), 964 (m), 941 (w), 902 (m), 861 (w)
cm−1; 1H NMR (400 MHz, CDCl3) δ 6.85 (s, 1H), 6.24 (s, 1H), 5.44
(s, 1H), 3.67−3.54 (m, 4H), 3.06−3.01 (m, 4H), 1.23 (t, J = 7.1 Hz,
6H), 1.07 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 151.5,
139.1, 125.1, 102.8, 96.7, 61.4, 45.1, 15.4, 11.8; HRMS Calcd for
+
C13H24NO3 [M + H]+ 242.17562, found 242.17495.
5-Diethoxymethyl-3-diethylamino-2-methylfuran (3b). Com-
pound 1b (0.201 g, 1.00 mmol) was reacted with diethylamine
E
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The Journal of Organic Chemistry
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+
96.8, 61.5, 54.3, 26.5, 24.3, 15.4, 12.2; HRMS Calcd for C15H26NO3
[M + H+] 268.19127, found 268.19248.
9.47 (s, 1H), 7.18 (s, 1H), 3.23 (septet, J = 7.0 Hz, 1H), 2.83 (q, J =
7.1 Hz, 4H), 1.27 (d, J = 7.0 Hz, 6H), 0.95 (t, J = 7.1 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 177.3, 163.1, 150.4, 133.2, 119.1, 50.3,
4-(5-Diethoxymethyl-2-methylfuran-3-yl)morpholine (3g). Com-
pound 1b (0.201 g, 1.00 mmol) was reacted with morpholine (0,087 g,
1.0 mmol). Isolation by FC (hexanes/ethyl acetate 90:10) provided
the title compound (0.177 g, 66%) as an orange liquid: IR (film) 1742
(m), 1634 (m), 1573 (m), 1526 (w), 1451 (s), 1404 (m), 1390 (m),
1374 (s), 1360 (s), 1342 (m), 1284 (m), 1263 (s), 1227 (s), 1162
(m), 1117 (s), 1098 (s), 1056 (s), 1009 (m), 988 (m), 956 (m), 917
(s), 850 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 6.32 (s, 1H), 5.40
(s, 1H), 3.65−3.62 (m, 4H), 3.59−3.53 (m, 4H), 2.83−2.80 (m, 4H),
2.25 (s, 3H), 1.23 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
148.6, 141.8, 134.5, 103.9, 96.8, 67.4, 61.6, 53.2, 15.4, 12.0; HRMS
+
26.0, 20.9, 13.2; HRMS Calcd for C12H20NO2 [M + H+] 210.14940,
found 210.14942.
4-Diethylamino-5-hexylfuran-2-carbaldehyde (4d). Furfural ace-
tal 3d (0.163 g, 0.500 mmol) was used. Isolation by FC (hexanes/ethyl
acetate 90:10) provided the title compound (0.100 g, 80%) as a
reddish liquid: IR (film) 1682 (s), 1601 (m), 1522 (s), 1475 (m),
1466 (m), 1449 (m), 1377 (m), 1360 (m), 1320 (m), 1293 (m), 1120
(m), 1085 (m), 969 (w), 901 (w) cm−1; 1H NMR (400 MHz, CDCl3)
δ 9.46 (s, 1H), 7.17 (s, 1H), 2.86 (q, J = 7.1 Hz, 4H), 2.68 (t, J = 7.7
Hz, 2H), 1.70−1.65 (m, 2H), 1.38−1.26 (m, 6H), 0.96 (t, J = 7.1 Hz,
6H), 0.90−0.86 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 177.2,
158.5, 150.4, 134.9, 119.1, 49.9, 31.7, 29.3, 27.7, 26.3, 22.7, 14.2, 13.1;
HRMS Calcd for C15H26NO2+ [M + H+] 252.19635, found 252.19785.
4-Diethylamino-5-phenylfuran-2-carbaldehyde (4e). Furfural ace-
tal 3e (0.159 g, 0.50 mmol) was used. Isolation by FC (hexanes/ethyl
acetate 90:10) provided the title compound (0.094 g, 78%) as an
orange liquid: IR (film) 3341 (w), 3063 (m), 3024 (m), 2756 (m),
1742 (m), 1678 (s), 1602 (s), 1589 (s), 1571 (s), 1520 (s), 1486 (s),
1473 (s), 1445 (s), 1423 (s), 1379 (s), 1360 (s), 1331 (s), 1306 (s),
1291 (s), 1245 (s), 1201 (s), 1181 (m), 1140(s), 1118 (s), 1086 (s),
1036 (s), 1020 (m), 995 (m), 922 (w), 873 (m), 842 (m), 782 (s),
+
Calcd for C14H24NO4 [M + H+] 270.17053, found 270.17177.
1-(5-Diethoxymethyl-2-methylfuran-3-yl)pyrrolidine (3h). Com-
pound 1b (0.200 g, 1.00 mmol) was reacted with pyrrolidine (0,071 g,
1.0 mmol). Isolation by FC (hexanes/ethyl acetate 90:10) provided
the title compound (0.152 g, 60%) as an orange liquid: IR (film) 3117
(w), 1742 (m), 1713 (m), 1637 (s), 1566 (s), 1523 (s), 1480 (s), 1443
(s), 1430 (s), 1404 (s), 1374 (s), 1359 (s), 1343 (s), 1295 (m), 1265
(s), 1198 (s), 1163 (s), 1118 (s), 1055 (s), 1011 (s), 990 (s), 956 (m),
940 (m), 904 (s), 873 (w) cm−1; 1H NMR (400 MHz, CDCl3) δ 6.20
(s, 1H), 5.40 (s, 1H), 3.6−3.53 (m, 4H), 3.11−3.08 (m, 4H), 2.36 (s,
3H), 1.90−1.87 (m, 4H), 1.23 (t, J = 7.0 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 147.8, 135.6, 133.1, 103.9, 96.8, 61.5, 52.0, 24.8, 15.4,
1
770 (s), 717 (s), 695 (s) cm−1; H NMR (400 MHz, CDCl3) δ 9.60
+
13.1; HRMS Calcd for C14H24NO3 [M + H+] 254.17562, found
(s, 1H), 8.19 (d, J = 7.3 Hz, 2H), 7.44−7.31 (m, 4H), 2.98 (q, J = 7.1
Hz, 4H), 1.03 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
177.7, 150.6, 150.0, 136.9, 130.1, 128.9, 128.7, 126.0, 118.8, 48.5, 12.6;
HRMS Calcd for C15H18NO2+ [M + H+] 244.13375, found 244.13344.
5-Methyl-4-(piperidin-1-yl)furan-2-carbaldehyde (4f). Furfural
acetal 3f (0.148 g, 0.55 mmol) was used. Isolation by FC (hexanes/
ethyl acetate 90:10) provided the title compound (0.081 g, 76%) as a
brownish red liquid: IR (film) 3341 (w), 3095 (w), 3024 (w), 1739
(m), 1677 (s), 1602 (s), 1517 (s), 1467 (m), 1452 (s), 1442 (s), 1384
(s), 1367 (s), 1329 (s), 1300 (w), 1284 (s), 1274 (m), 1260 (m), 1242
(m), 1231 (m), 1174 (m), 1130 (s), 1110 (s), 1063 (m), 1039 (m),
1026 (m), 1000 (m), 950 (m), 908 (m), 861 (m), 837 (m), 781 (s),
254.17758.
Stability Study. A sample of 3b was kept at rt with open access to
moist air, and the compound was analyzed by TLC at intervals.
Gradually two products appeared to be formed, and after 28 days the
two compounds were isolated by FC (hexanes/ethyl acetate 90:10)
after proton NMR spectra of the product mixture had been recorded.
The main product was 4-diethylamino-5-methylfuran-2-carbaldehyde
(4b), which was isolated pure as a reddish liquid, whereas the minor
product, a yellowish liquid, tentatively was given the structure 1,1-
diethoxy-4-diethylaminohex-3-ene-2,5-dione (5) on the basis of NMR
and IR spectra of an impure sample of the compound. The
composition of the product mixture was determined from its proton
NMR spectra and the individual spectra of 3b, 4b and 5. Data for 4b:
IR (film) 3341 (w), 3100 (w), 1680 (s), 1604 (s), 1522 (s), 1477 (s),
1448 (s), 1374 (s), 1356 (m), 1315 (s), 1248 (m), 1117 (s), 1088 (s),
1
712 (s) cm−1; H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 7.11 (s,
1H), 2.82−2.79 (m, 4H), 2.37 (s, 3H), 1.72−1.66 (m, 4H), 1.56−1.50
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 176.9, 150.2, 149.8, 139.2,
116.9, 54.0, 26.3, 24.1, 12.8; HRMS Calcd for C11H16NO2+ [M + H+]
194.11810, found 194.11694.
1067 (m), 1031 (w), 1000 (m), 947 (m), 887 (w) cm−1; H NMR
1
5-Methyl-4-(morpholine-4-yl)furan-2-carbaldehyde (4g). Furfural
acetal 3g (0.134 g, 0.500 mmol) was used. Isolation by FC (hexanes/
ethyl acetate 90:10) provided the title compound (0.074 g, 76%) as an
orange liquid: IR (film) 3341 (w), 3099 (m), 2688 (m), 1732 (m),
1673 (s), 1603 (s), 1519 (s), 1452 (s), 1392 (m), 1375 (s), 1329 (s),
1304 (s), 1288 (m), 1275 (s), 1265 (s), 1242 (m), 1222 (m), 1210
(m), 1182 (m), 1116 (s), 1071 (m), 1044 (m), 1030 (m), 1001 (m),
951 (m), 918 (s), 848 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 9.45
(s, 1H), 7.13 (s, 1H), 3.83−3.81 (m, 4H), 2.88−2.86 (m, 4H), 2.38 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 176.9, 150.4, 150.0, 137.8,
(400 MHz, CDCl3) δ 9.45 (s, 1H), 7.15 (s, 1H), 2.88 (q, J = 7.1 Hz,
4H), 2.34 (s, 3H), 0.97 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 177.1, 154.0, 150.2, 135.2, 118.9, 49.5, 13.0, 12.3; HRMS
+
Calcd for C10H16NO2 [M + H+] 182.11810, found 182.11676.
Conversion of Furfural Diethyl Acetals 3 to Furfurals 4;
General Procedure. Aminofuran 3 (0.5−1.0 mmol) was dissolved in
a 7:3 mixture of THF and H2O (5 mL). p-Toluenesulfonic acid
monohydrate (0.019 g, 0.10 mmol) was added, and the mixture was
stirred at 40 °C for 1 h. Most of the THF was then evaporated under
reduced pressure, and to the residue was added a saturated aqueous
solution of NaCl (2 mL) and DCM (2 mL). The phases were
separated, and the aqueous phase was extracted with DCM (3 × 3
mL). The combined extracts were washed with a saturated aqueous
solution of NaHCO3 (5 mL), dried (MgSO4), filtered and evaporated
under reduced pressure. The crude product was isolated by FC
(hexanes/ethyl acetate) to give the corresponding furfural 4.
4-Diethylamino-5-methylfuran-2-carbaldehyde (4b). Furfural
acetal 3b (0.256 g, 1.00 mmol) was used. Isolation by FC (hexanes/
ethyl acetate 90:10) provided the title compound (0.140 g, 77%) as a
reddish liquid. The spectroscopic and spectrometric data were
identical to those reported above.
+
116.3, 67.1, 52.8, 12.6; HRMS Calcd for C10H14NO3 [M + H+]
196.09737, found 196.09791.
5-Methyl-4-(pyrrolidin-1-yl)furan-2-carbaldehyde (4h). Furfural
acetal 3h (0.101 g, 0.400 mmol) was used. Isolation by FC
(hexanes/ethyl acetate 80:20) provided 4h (0.046 g, 55%) as a red
liquid: IR (film) 3431 (w), 3325 (w), 3185 (w), 3100 (w), 2706 (w),
1763 (m), 1738 (s), 1672 (s), 1606 (s), 1513 (s), 1489 (s), 1445 (s),
1394 (m), 1368 (s), 1335 (s), 1271 (m), 1247 (m), 1214 (s), 1170
(s), 1108 (s), 1059 (m), 1002 (m), 956 (m), 914 (w) cm−1; 1H NMR
(400 MHz, CDCl3) δ 9.40 (s, 1H), 6.91 (s, 1H), 3.19−3.15 (t, J = 6.4
Hz, 4H), 2.48 (s, 3H), 1.98−1.91 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 176.8, 149.3, 143.7, 136.6, 114.8, 51.4, 25.1, 13.9; HRMS
4-Diethylamino-5-isopropylfuran-2-carbaldehyde (4c). Furfural
acetal 3c (0.267 g, 0.940 mmol) was used. Isolation by FC
(hexanes/ethyl acetate 90:10) provided the title compound (0.175 g,
89%) as a deep orange liquid: IR (film) 3099 (w), 1683 (s), 1600 (m),
1525 (s), 1477 (m), 1450 (m), 1378 (s), 1330 (s), 1307 (m), 1285
(m), 1244 (m), 1232 (m), 1133 (m), 1104 (m), 1080 (s), 1063 (m),
+
Calcd for C10H14NO2 [M + H+] 180.10245, found 180.10193.
One-Pot Synthesis of 4b. A solution of 1b (2.13 g, 10.6 mmol) in
ethanol (50 mL) was mixed with diethylamine (0.78 g, 10.6 mmol),
and the mixture was stirred for 1 h at rt. The ethanol was removed on
a rotary evaporator, and to the residue a solution of p-TsOH hydrate
(0.40 g, 2.11 mmol) in a 3:1 mixture of THF and water (100 mL) was
1
1044 (w), 964 (m), 867 (w) cm−1; H NMR (400 MHz, CDCl3) δ
F
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The Journal of Organic Chemistry
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added. The resulting mixture was stirred at 40 °C for 1 h. Most of the
THF was then evaporated under reduced pressure on a rotary
evaporator, and to the residue was added DCM (20 mL) and a
saturated aqueous solution of NaCl (20 mL). The phases were
separated, and the aqueous phase was extracted with DCM (3 × 30
mL). The extracts were washed with a saturated aqueous solution of
NaHCO3 (50 mL), dried (MgSO4), filtered and evaporated under
reduced pressure on a rotary evaporator. From the residue 4b (1.36 g,
73%) was isolated pure by FC (hexanes/ethyl acetate 90:10) as a
reddish liquid. The spectroscopic data were identical to those reported
above.
3-Ethoxy-5-diethoxymethyl-N,N-diethyl-2,3-dihydro-2,2-di-
methylfuran-3-amine (6) and 5-Diethoxymethyl-2,2-dimethyl-
furan-3(2H)-one (7). 1,1-Diethoxy-5-hydroxy-5-methyl-hex-3-yn-2-
one4 (0.214 g, 1.00 mmol) was dissolved in ethanol (5 mL), and
diethylamine (0.073 g, 1.0 mmol) was added under stirring at rt in the
presence of air. The mixture was stirred at rt for 1 h, and the solvent
was then evaporated, and essentially pure 6 (0.272 g, 86%) was
obtained as an orange liquid.
ethyl acetate 70:30) gave 8b (0.080 g, 60%) as a yellow liquid: IR
(ATR) 1762 (m), 1710 (m), 1593 (m), 1575 (w), 1509 (s), 1445 (s),
1360 (m), 1320 (s), 1252 (m), 1134 (m), 1105 (m), 1024 (m), 977
1
(m), 953 (m), 908 (w), 853 (m), 777 (w), 734 (s) 692 (s) cm−1; H
NMR (400 MHz, CDCl3) δ 7.43 (d, 2H), 7.36−7.30 (m, 3H), 6.91 (d,
J = 16.3 Hz, 1H), 6.76 (d, J = 16.3 Hz, 1H), 6.28 (s, 1H), 2.82−2.79
(m, 4H), 2.32 (s, 3H), 1.69−1.68 (m, 4H), 1.56−1.53 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 149.8, 128.7, 128.3, 126.8, 126.1, 125.2,
117.0, 54.3, 26.3, 12.3; MS (DART+) m/z 268 (95, [M+H]+); HRMS
Calcd for C18H22NO+ [M + H+] 268.17014, found 268.17035.
3-(Morpholine-4-yl)-2-methyl-5-(2-phenylethen-1E-yl)furan (8c).
Furfural 4g (0.020 g, 0.10 mmol) was reacted with BTPB (0.041 g,
0.10 mmol) and a 50% aqueous solution of NaOH (0.1 mL). The
reaction mixture was stirred for 20 min. Isolation by FC (hexanes/
ethyl acetate 70:30) gave 8c (0.03 g, 90%) as an orange liquid: IR
(ATR) 3026 (w), 1710 (m), 1596 (s), 1576 (m), 1517 (s), 1494 (m),
1446 (s), 1415 (m), 1318 (m), 1300 (m), 1264 (s), 1155 (m), 1102
(s), 1070 (m), 1043 (m), 985 (w), 952 (s), 916 (s), 845 (m), 786 (m),
748 (s) 691 (s), 580 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.44 (d,
2H), 7.35−7.31 (m, 2H), 7.25−7.20 (m, 1H), 6.93 (d, J = 16.2 Hz,
1H), 6.77 (d, J = 16.3 Hz, 1H), 6.28 (s, 1H), 3.82−3.80 (m, 4H),
2.87−2.85 (m, 4H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
150.0, 128.8, 128.2, 127.4, 126.3, 125.7, 116.6, 104.5, 67.4, 53.3, 12.2;
The compound remained unchanged when stored in a vial at rt and
below. When spread over a glass plate and exposed to laboratory air, it
was gradually converted to 5-(diethoxymethyl)-2,2-dimethylfuran-
3(2H)-one (7) in quantitative yield. The rate was of course dependent
on how thin the liquid layer was. Data for 6: IR (film) 3392 (s), 1759
(s), 1708 (s), 1621 (s), 1594 (s), 1456 (s), 1375 (s), 1334 (m), 1280
(m), 1246 (m), 1163 (s), 1111 (s), 1068 (s), 988 (s), 952 (m), 913
(m), 895 (m), 822 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 4.23 (s,
1H), 4.11 (s, 1H), 3.80−3.62 (m, 4H), 3.52−3.44 (m, 2H), 3.18−3.00
(m, 4H), 1.66−1.49 (m, 6H), 1.27−1.06 (m, 15H); 13C NMR (100
MHz, CDCl3) δ 156.3, 111.9, 106.0, 89.1, 84.6, 65.4, 65.3, 56.9, 43.9,
28.8, 28.0, 15.9, 15.6, 15.5, 12.7; HRMS Calcd for C15H28NO3+ [M −
OEt]+ 270.20692, found 270.20806. Data for 7: IR (film) 3483 (s),
1757 (s), 1709 (s), 1605 (s), 1457 (s), 1377 (s), 1334 (m), 1301 (s),
1268 (s), 1170 (s), 1154 (s), 1110 (s), 1064 (s), 974 (s), 952 (m), 904
(m), 864 (m), 840 (m), 820 (m) cm−1; 1H NMR (400 MHz, CDCl3)
δ 5.70 (s, 1H), 5.24 (s, 1H), 3.72−3.60 (m, 4H), 1.4(s, 6H), 1.26 (t, J
= 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 207.3, 185.5, 102.8,
+
+
MS (ESI+) m/z 270 (25, [M+H] ); HRMS Calcd for C17H20NO2
[M + H+] 270.14940, found 270.14958.
3-Diethylamino-2-phenyl-5-(2-phenylethen-1E-yl)furan (8d).
Furfural 4e (0.12 g, 0.50 mmol) was reacted with BTPB (0.44 g, 1.0
mmol) and a 50% aqueous solution of NaOH (0.4 mL). The reaction
mixture was stirred for 2 h. Isolation by FC (hexanes/ethyl acetate
90:10) to obtain the title compound 8d (0.080 g, 50%) as a yellowish
liquid: IR (ATR) 3056 (w), 3030 (w), 1949, (w), 1882 (w), 1808 (w),
1678 (m), 1630 (m), 1596 (m), 1585 (s), 1565 (m), 1522 (m), 1487
(m), 1474 (m), 1414 (m), 1327 (m), 1291 (m), 1200 (m), 1178 (m),
1119 (m), 1064 (m), 1023 (m), 984 (m), 976 (m), 958 (m), 912 (m),
873 (m), 850 (m), 801 (s), 787 (w), 765 (m), 749 (s), 702 (m), 692
(s) cm−1; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, 2H), 7.48 (d, 2H),
7.40−7.32 (m, 4H), 7.25−7.18 (m, 2H), 7.10 (d, J = 16.3 Hz, 1H),
6.85 (d, J = 16.3 Hz, 1H), 6.47 (s, 1H), 2.95−2.91 (m, 4H), 1.06−1.02
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 150.8, 144.6, 137.3, 136.3,
131.6, 128.9, 128.4, 127.6, 126.9, 126.4, 124.6, 124.4, 116.8, 107.9,
48.9, 12.8; MS (ESI+) m/z 318 (18, [M + H]+); HRMS Calcd for
C22H24NO+ [M + H+] 318.18579, found 318.18578.
+
96.4, 89.5, 62.0, 22.9, 15.2; HRMS Calcd for C11H19NO4 [M + H+]
215.12833, found 215.12662.
Synthesis of Styrene Derivatives 8 from Furfural 4 by Wittig
Reaction; General Procedure. To a flask equipped with magnetic
stirrer and condenser were transferred furfural 4 (1.0−0.10 mmol),
DCM (4 mL), benzyltriphenylphosphonium bromide (BTPB) (1.0
equiv) and water (2 mL). The mixture was stirred vigorously for some
5 min, and then a 50% aqueous solution of NaOH (0.1−0.4 mL) was
added dropwise. The reaction mixture was stirred for 20 min at rt in all
cases except one. After addition of DCM (3 mL) and H2O (5 mL), the
phases were separated, and the aqueous phase was extracted with
DCM (3 × 5 mL). The combined organic phases were dried
(MgSO4), filtered and concentrated under reduced pressure on the
rotary evaporator (40 °C). Purification by FC with mixtures of hexanes
and ethyl acetate as eluent provided the following compounds.
3-Diethylamino-2-methyl-5-(2-phenylethen-1E-yl)furan (8a).
Furfrual 4b (0.181 g, 1.00 mmol) was reacted with BTPB (0.433 g,
1.00 mmol) and a 50% aqueous solution of NaOH (0.4 mL). The
reaction mixture was stirred for 20 min. Isolation by FC (hexanes/
ethyl acetate 80:20) gave 8a (0.227 g, 89%) as an orange liquid: IR
(ATR) 3024 (w), 1711 (m), 1596 (s), 1576 (w), 1514 (s), 1464 (m),
1445 (m), 1375 (m), 1355 (m), 1196 (m), 1139 (m), 1108 (s), 1026
Synthesis of Ethyl Acrylate Derivatives 8 from Furfural 4 by
Emmons−Horner−Wadsworth Reaction; General Procedure. A
dried 25-mL, two-necked, round-bottom flask equipped with magnetic
stirrer and condenser was charged with triethyl phosphonoacetate
(TPA) (0.11 g, 0.50 mmol) and dry THF (8 mL). The mixture was
cooled to −78 °C before a 1.6 M solution of BuLi in hexane (0.25 mL,
0.40 mmol) was added under N2. The reaction mixture was stirred at
−78 °C for some 20 min, and furfural 4 (0.070 g, 0.40 mmol) in dry
THF (3 mL) was then added dropwise. When the addition was
complete the cooling was removed, and the mixture was stirred for
approximately 4 h while the temperature reached rt. The reaction was
quenched with a saturated aqueous solution of NH4Cl (12 mL) and
was then worked up by extraction with DCM (3 × 10 mL). The
combined organic phases were dried (MgSO4), filtered and
concentrated under reduced pressure on a rotary evaporator (40
°C). Purification of the crude product using FC with mixtures of
hexanes and ethyl acetate as eluent provided the following products.
Ethyl (2E)-3-(4-Diethylamino-5-methylfuran-2-yl)prop-2-enoate
(8e). TPA (0.11 g, 0.50 mmol) was reacted with furfural 4b (0.070
g, 0.40 mmol). Isolation by FC (hexane/ethyl acetate 80:20) gave 8e
(0.060 g, 60%) as a yellow liquid: IR (ATR) 1706 (s), 1631 (s), 1585
(s), 1567 (m), 1467 (m), 1445 (m), 1379 (m), 1294 (m), 1261 (s),
1159 (s), 1111 (m), 1066 (m), 1035 (m), 995 (w), 967 (m), 920 (w),
1
(m), 997 (m), 953 (m), 790 (m), 748 (s), 697 (s) cm−1; H NMR
(400 MHz, CDCl3) δ 7.40 (d, 2H), 7.32 (t, 2H), 7.21 (t, 1H), 6.93 (d,
J = 16.2 Hz, 1H), 6.78 (d, J = 16.2 Hz, 1H), 6.28 (s, 1H), 2.85−2.80
(m, 4H), 2.28 (s, 3H), 0.97 (t, 6H); 13C NMR (100 MHz, CDCl3) δ
149.1, 145.5, 136.5, 131.9, 127.8, 126.3, 125.3, 124.2, 116.1, 105.4,
49.2, 12.2, 10.6; MS (DART+) m/z 256 (100, M++H); HRMS Calcd
for C17H22NO+ [M + H+] 256.17014, found 256.17000.
1
856 (m), 818 (m) cm−1; H NMR (400 MHz, CDCl3) δ 7.30 (d, J =
3-(Piperidin-1-yl)-2-methyl-5-(2-phenylethen-1E-yl)furan (8b).
Furfural 4f (0.10 g, 0.50 mmol) was reacted with BTPB (0.22 g,
0.50 mmol) and a 50% aqueous solution of NaOH (0.2 mL). The
reaction mixture was stirred for 20 min. Isolation by FC (hexanes/
15.6 Hz, 1H), 6.52 (s, 1H), 6.20 (d, J = 15.6 Hz, 1H), 4.25−4.20 (m,
2H), 2.85 (m, 4H), 2.27 (s, 3H), 1.83−1.29 (m, 3H), 0.97−0.93 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 167.6, 149.5, 147.9, 134.0,
131.4, 113.7, 112.7, 60.4, 49.9, 14.5, 13.1, 11.8; MS (DART+) m/z 252
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+
(100, M++H); HRMS Calcd for C14H22NO3 [M + H+] 252.15997,
found 252.15969.
1211 (s), 1155 (s), 1121 (s), 1084 (s), 1062 (s), 1006 (s), 950 (m),
921 (m), 882 (w), 832 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.96
(s, 1H), 7.44 (s, 1H), 2.90 (q, J = 7.1 Hz, 4H), 2.37 (s, 3H), 0.98 (t, J
= 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 174.5, 154.0, 148.2,
Ethyl (2E)-3-(5-Methyl-4-(piperidin-1-yl)furan-2-yl)prop-2-enoate
(8f). TPA (0.11 g, 0.50 mmol) was reacted with furfural 4f (0.10 g,
0.50 mmol). Isolation by FC (hexane/ethyl acetate 80:20) gave the
title compound 8f (0.11 g, 84%) as a yellow/orange liquid: IR (ATR)
1771 (w), 1702 (s), 1638 (m), 1594 (s), 1519 (m), 1443 (m), 1365
(m), 1320 (m), 1299 (m), 1256 (s), 1227 (m), 1162 (s), 1127 (s),
1107 (s), 1030 (m), 1026 (m), 1000 (w), 968 (m), 943 (w), 908 (m),
+
147.6, 134.4, 119.8, 49.8, 12.8, 12.5; HRMS Calcd for C11H17N2O3
[M + H+] 225.12392, found 225.12374.
1-(4-Diethylamino-5-methylfuran-2-yl)propan-1-one (9b).
Furfural 4b (0.181 g, 1.0 mmol) was reacted with nitroethane
(0.150 g, 2.0 mmol) in the presence of Et3N (0.101 g, 1.0 mmol) for
12 h. Isolation by FC (hexanes/ethyl acetate 90:10) using Et3N-
washed SiO2 as stationary phase gave unreacted 4b (0.02 g, 11%) as a
yellowish oil and 9b (0.080 g, 38%) as a yellow liquid: IR (ATR) 3100
(w), 1714 (w), 1669 (s), 1609 (s), 1518 (s), 1447 (m), 1376 (w),
1354 (m), 1262 (m), 1116 (s), 1086 (m), 1032 (m), 902 (s), 799 (s)
856 (m) 807 (m) cm−1; H NMR (400 MHz, CDCl3) δ 7.28 (d, J =
1
15.6 Hz, 1H), 6.50 (s, 1H), 6.18 (d, J = 15.6 Hz, 1H), 4.25−4.19 (m,
2H), 2.79−2.77 (m, 4H), 2.30 (s, 3H), 1.68−1.64 (m, 6 H), 1.32−1.29
(m, 3 H); 13C NMR (100 MHz, CDCl3) δ 171.3, 167.6, 147.4, 144.9,
138.4, 131.3, 113.4, 111.0, 60.5, 60.3, 54.1, 26.3, 24.1, 21.2, 14.5, 14.3,
12.5; MS (DART+) m/z 264 (100, M++H); HRMS Calcd for
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 2.86 (q, J = 7.1
C15H22NO3 [M + H+] 264.15997, found 264.15969.
+
Hz, 4H), 2.79 (q, J = 7.4 Hz, 2H), 2.31 (s, 3H), 1.20 (t, J = 7.4 Hz,
3H), 0.96 (t, J = 7.1, 6H); 13C NMR (100 MHz, CDCl3) δ 189.9,
151.8, 149.8, 134.4, 114.6, 49.9, 31.3, 13.2, 12.2, 8.8; MS (DART+) m/
z 210 (M + H+); HRMS Calcd for C12H20NO2+ [M + H]+ 210.14940,
found 210.15039.
Ethyl (2E)-3-(5-Methyl-4-(morpholin-4-yl)furan-2-yl)prop-2-
enoate (8g). TPA (0.040 g, 0.20 mmol) was reacted with furfural
4g (0.040 g, 0.20 mmol). Isolation by FC (hexane/ethyl acetate 80:20)
gave 8g (0.050 g, 85%) as an orange liquid: IR (ATR) 1768 (m), 1712
(s), 1639 (m), 1597 (m), 1516 (s), 1442 (m), 1366 (m), 1298 (m),
1256 (m), 1230 (m), 1156 (s), 1110 (s), 1015 (m), 971 (m), 918 (m),
1-(4-Diethylamino-5-phenylfuran-2-yl)propan-1-one (9c).
Furfural 4e (0.243 g, 1.00 mmol) was reacted with nitroethane
(0.150 g, 2.00 mmol) in the presence of Et3N (0.101 g, 1.00 mmol) for
24 h. Isolation by FC using Et3N-washed SiO2 as stationary phase and
hexanes/ethyl acetate 90:10 as eluent gave unreacted 4e (0.030 g,
12%) as a yellowish oil and 9c (0.10 g, 37%) as an orange liquid: IR
(ATR) 3319 (w), 3064 (w), 1669 (s), 1592 (m), 1571 (m), 1519 (s),
1485 (s), 1444 (s), 1415 (m), 1377 (m), 1359 (m), 1273 (m), 1204
(m), 1140 (s), 1084 (m), 1071 (m), 1027 (s), 918 (m), 900 (s), 844
880 (w) cm−1; H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 15.7 Hz,
1
1H), 6.50 (s, 1H), 6.21 (d, J = 15.7 Hz, 1H), 4.25−4.20 (m, 2H),
3.82−3,79 (m, 4H), 2.85−2.83 (m, 4H), 2.31 (s, 3H), 1.33−1.29 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 167.5, 147.8, 145.4, 137.1,
131.1, 114.1, 110.5, 67.2, 60.4, 52.9, 30.8, 14.4, 12.8; MS (DART+) m/
+
z 266 (100, M++H); HRMS Calcd for C14H20NO4 [M + H+]
266.13923, found 266.13945.
1
(w), 799 (m), 768 (s), 712 (m), 692 (s) cm−1; H NMR (400 MHz,
Ethyl (2E)-3-(4-Diethylamino-5-phenylfuran-2-yl)prop-2-enoate
(8h). TPA (0.22 g, 1.0 mmol) was reacted with furfural 4e (0.23 g,
0.95 mmol). Isolation by FC (hexane/ethyl acetate 80:20) furnished
8h (0.25 g, 84%) as a yellowish liquid: IR (ATR) 1702 (s), 1632 (s),
1584 (m), 1567 (m), 1520 (m), 1488 (m), 1479 (w), 1450 (m), 1365
(m), 1294 (m), 1261 (s), 1236 (m), 1154 (s), 1133 (m), 1093 (w),
1034 (s), 995 (w), 967 (m), 917 (w), 877 (w), 856 (m), 818 (m), 766
(m), 714 (m), 692 (s), 671 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ
8.11 (d, 2H), 7.41−7.37 (m, 3H), 7.36−7.25 (3H), 6.70 (s, 1H), 6.38
(d, J = 15.6 Hz, 1H), 4.28−4.23 (m, 2H), 2.96−2.91 (m, 4H), 1.35−
1.32 (m, 3H), 1.04−1.01 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
167.7, 148.6, 136.8, 131.0, 128.7, 127.1, 125.1, 115.4, 113.8, 111.4,
60.3, 48.6, 26.3, 14.6, 13.0; MS (DART+) m/z 314 (100, [M + H+]);
HRMS Calcd for C19H24NO3+ [M + H+] 314.17562, found 314.17586.
Henry Reactions with Furfurals 4b and 4e; General
Procedure. Furfural 4 (0.5−1.0 mmol) in water (5 mL) was stirred
at rt in a flask equipped with condenser. Nitroalkane (1.0−2.2 mmol)
and Et3N (1.0−1.2 mmol) were added, and the reaction mixture was
kept stirring for about 6−24 h at rt. Water (10 mL) and Et2O (10 mL)
were added, the phases were separated, and the aqueous phase was
extracted with Et2O (3 × 10 mL). The combined organic phases were
dried (MgSO4), filtered and concentrated under reduced pressure on
the rotary evaporator (40 °C). The product(s) were isolated by FC of
the residue using mixtures of hexanes and ethyl acetate as eluents.
1-(4-Diethylamino-5-methylfuran-2-yl)ethanone (9a) and 3-
Diethylamino-5-hydroxyiminoacetyl-2-methylfuran (10). Fur-
fural 4b (0.181 g, 1.0 mmol) was reacted with nitromethane (0.122 g,
2.0 mmol) in the presence of Et3N (0.101 g, 1.0 mmol) for 6 h.
Isolation by FC (hexanes/ethyl acetate 90:10) furnished 9a (0.128 g,
66%) as a red liquid and 10 (0.041 g, 18%) as a dark red semisolid
with no clear melting point. Data for 9a: IR (film) 3326 (w), 3103
(w), 1746 (m), 1714 (s), 1673 (s), 1611 (a), 1526 (s), 1473 (s), 1448
(s), 1423 (s), 1360 (s), 1315 (s), 1286 (s), 1227 (s), 1195 (m), 1152
(s), 1120 (s), 1088 (s), 1022 (m), 994 (m), 941 (m), 919 (m), 890
(w), 843 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.10 (s, 1H), 2.86
(q, J = 7.1 Hz, 4H), 2.42 (s, 3H), 2.32 (s, 3H), 0.96 (t, J = 7.1 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 186.2, 152.0, 149.9, 134.5,
115.1, 49.7, 25.6, 13.0, 12.1; HRMS Calcd for C11H18NO2+ [M + H]+
196.13375, found 196.13449. Data for 10: IR (film) 3267 (s), 3046
(s), 1965 (w), 1853 (w), 1840 (w), 1714 (m), 1644 (s), 1599 (s),
1555 (s), 1516 (s), 1453 (s), 1379 (s), 1337 (s), 1268 (s), 1229 (s),
CDCl3) δ 8.16 (d, J = 7.6 Hz, 2H), 7.43−7.28 (m, 3H), 7.24 (s, 1H),
2.98−2.89 (m, 6H), 1.24 (t, J = 7.4 Hz, 3H), 1.02 (t, J = 7.1 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 190.6, 149.9, 148.4, 136.6, 130.7,
128.7, 128.4, 125.8, 115.0, 48.8, 31.6, 12.8, 8.6; MS (EI+) m/z 271.2
+
(M+), 256.1 (100, M − CH3); HRMS Calcd for C17H22NO2 [M +
H+] 272.16505, found 272.16588.
1-(4-Diethylamino-5-methylfuran-2-yl)pentan-1-one (9d).
Furfural 4b (0.097 g, 0.50 mmol) was reacted with 1-nitrobutane
(0.110 g, 1.0 mmol) in the presence of Et3N (0.054 g, 0.5 mmol) for
24 h. Isolation by FC using Et3N-washed SiO2 as stationary phase and
hexanes/ethyl acetate 90:10 as eluent unreacted starting material 4b
(0.023 g, 13%) and 9d (0.023 g, 18%): IR (ATR) 3103 (w), 1744 (w),
1718 (w), 1668 (s), 1610 (m), 1519 (s), 1446 (m), 1375 (m), 1355
(m), 1282 (m), 1231 (m), 1116 (s), 1082 (s), 1039 (s), 915 (m), 870
(w), 843 (m) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.09 (s, 1H), 2.85
(q, J = 7.1 Hz, 4H), 2.75 (t, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.69 (m,
2H), 1.40 (m, 2H), 0.96 (t, J = 7.1 Hz, 6H), 0.94 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 189.5, 152.0, 150.0, 134.4, 114.8, 49.9,
37.9, 27.1, 22.8, 14.2, 13.2, 12.3; MS (EI+) m/z 237.2 (M+), 222.2
(100, M − CH3); HRMS Calcd for C14H24NO2+ [M + H+] 238.18070,
found 238.18088.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: leiv.sydnes@kj.uib.no.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Research Council of Norway, the
University of Bergen and the Munin Foundation is highly
■
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appreciated. Recording of mass spectra by Dr. Bjarte Holmelid
is sincerely acknowledged. Thanks are also due to Professor
Victor S. Martin and his research group at the Universidad de
La Laguna, Tenerife, Spain, for excellent working conditions
during a sabbatical stay.
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